A Clinical Study Evaluating the Safety, Tolerability, and Initial Efficacy of Single Intravenous Infusion of JWK007 in Patients With Duchenne Muscular Dystrophy (DMD)

Duchenne Muscular Dystrophy Clinical Trial

Official title:

A Clinical Study Evaluating the Safety, Tolerability, and Initial Efficacy of Single Intravenous Infusion of JWK007 in Patients With Duchenne Muscular Dystrophy (DMD)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06114056
• Other study ID #: 2023-1285
• Status: Recruiting
• Phase: Phase 1
• Start date: January 22, 2024
• Est. completion date: December 31, 2028

Study information

• Verified date: January 2024
• Source: West China Hospital
• Contact: Xingchen Peng, Ph.D
• Phone: +8618980606753
• Email: pxx2014[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a single-center, single-arm, non-randomized, open-label, non-controlled, dose-escalation, prospective clinical trial designed to assess the safety, tolerability, and preliminary efficacy of JWK007 injection in pediatric patients with Duchenne Muscular Dystrophy (DMD).

Description:

DMD is a rare genetic disorder that primarily affects males. This disease is closely associated with mutations in the DMD gene located on the X chromosome. The DMD gene encodes a protein known as dystrophin, which plays a crucial role in providing essential structural and protective support within the muscles. Gene therapy drugs using Adeno-Associated Virus (AAV) as a vector hold the promise of offering a convenient, effective, and safe treatment option for DMD patients. Therefore, we have independently developed and designed the JWK007 injection. The study will include two dosing groups and employ a '3+3' dose escalation design, incrementally increasing dosages in a sequential, ascending manner.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 6
• Est. completion date: December 31, 2028
• Est. primary completion date: June 30, 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 5 Years to 10 Years

Eligibility

Inclusion Criteria:

Participants meeting all of the following criteria may be considered for inclusion:

1. Male, aged 5 to 10 years (inclusive).

2. Diagnosis of Duchenne Muscular Dystrophy (DMD) confirmed through medical history and genetic testing, characterized by a frameshift mutation (deletion or duplication) or a premature stop codon mutation in the DMD gene between exons 18 to 58.

3. Below-average performance on motor assessment testing.

4. Ability to cooperate with motor assessment testing.

5. Tolerance for muscle biopsy under anesthesia with no contraindications for biopsy.

6. Participants must have been taking a stable dose of oral corticosteroids for at least 12 weeks prior to screening, and the expected dose should remain constant throughout the study, except for adjustments related to changes in body weight.

Exclusion Criteria:

Participants meeting any one of the following criteria are not eligible for inclusion:

1. Active viral infection based on clinical observations.

2. Signs of cardiomyopathy, including echocardiogram with ejection fraction below 40%.

3. Serological evidence of HIV infection, or Hepatitis B or C infection.

4. Diagnosis of (or ongoing treatment for) an autoimmune disease.

5. Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin = 3.0 mg/dL, creatinine = 1.8 mg/dL, Hgb < 80 or > 180 g/L; WBC > 18.5*10^9/L).

6. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer.

7. Subjects with AAVrh74 neutralizing antibody titers > 1:400 as determined by ELISA immunoassay.

8. Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's wellbeing, safety, or clinical interpretability.

9. Severe infection (eg. pneumonia, pyelonephritis, or meningitis) within 4 weeks before gene transfer visit (enrollment may be postponed).

10. Has received any investigational medication (other than corticosteroids) or exon skipping medications (including ExonDys 51), experimental or otherwise, in the last 6 months prior to screening for this study.

11. Has had any type of gene therapy, cell based therapy (eg. stem cell transplantation), or CRISPR/Cas9.

12. Family does not want to disclose patient's study participation with primary care physician and other medical providers

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Biological:
• JWK007 Single intravenous infusion administration
Six male children aged 5-10 years were enrolled in the study. The patients were divided into two different dose groups, and a "3+3" dose escalation design was used, the low dose was 1.0×1014vg/kg, and the high dose was 2.0×1014vg/kg. Only one intravenous infusion of JWK007 was administered to each patient.

Locations

Country	Name	City	State
China	West China Hospital, Sichuan University	Chengdu	Sichuan

Sponsors (1)

Lead Sponsor	Collaborator
West China Hospital

Country where clinical trial is conducted

China, 

References & Publications (6)

Duan D. Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy. Mol Ther. 2018 Oct 3;26(10):2337-2356. doi: 10.1016/j.ymthe.2018.07.011. Epub 2018 Jul 17. — View Citation

Mendell JR, Sahenk Z, Lehman K, Nease C, Lowes LP, Miller NF, Iammarino MA, Alfano LN, Nicholl A, Al-Zaidy S, Lewis S, Church K, Shell R, Cripe LH, Potter RA, Griffin DA, Pozsgai E, Dugar A, Hogan M, Rodino-Klapac LR. Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. JAMA Neurol. 2020 Sep 1;77(9):1122-1131. doi: 10.1001/jamaneurol.2020.1484. — View Citation

Miesbach W, Meijer K, Coppens M, Kampmann P, Klamroth R, Schutgens R, Tangelder M, Castaman G, Schwable J, Bonig H, Seifried E, Cattaneo F, Meyer C, Leebeek FWG. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018 Mar 1;131(9):1022-1031. doi: 10.1182/blood-2017-09-804419. Epub 2017 Dec 15. — View Citation

Roberts TC, Wood MJA, Davies KE. Therapeutic approaches for Duchenne muscular dystrophy. Nat Rev Drug Discov. 2023 Nov;22(11):917-934. doi: 10.1038/s41573-023-00775-6. Epub 2023 Aug 31. — View Citation

Verdera HC, Kuranda K, Mingozzi F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. Mol Ther. 2020 Mar 4;28(3):723-746. doi: 10.1016/j.ymthe.2019.12.010. Epub 2020 Jan 10. — View Citation

Xue F, Li H, Wu X, Liu W, Zhang F, Tang D, Chen Y, Wang W, Chi Y, Zheng J, Du Z, Jiang W, Zhong C, Wei J, Zhu P, Fu R, Liu X, Chen L, Pei X, Sun J, Cheng T, Yang R, Xiao X, Zhang L. Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial. Lancet Haematol. 2022 Jul;9(7):e504-e513. doi: 10.1016/S2352-3026(22)00113-2. Epub 2022 May 19. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	adverse events	Adverse events defined as the number of participants with adverse events according CTCAE v5.0	5 years
Secondary	North Star Ambulatory Assessment	North Star Ambulatory Assessment (NSAA) is a clinical tool used to assess the motor function and ambulatory capabilities of children and adolescents with neuromuscular disorders like Duchenne muscular dystrophy.	5 years
Secondary	Six-Minute Walk Test	the distance the patient walked in six minutes	5 years
Secondary	10-Meter Walk/Run Test	The time it takes to walk 100 meters	5 years
Secondary	creatine kinase	Changes in circulating levels of CK	5 years
Secondary	the expression of micro-dystrophin gene	Baseline muscle biopsies for dystrophin expression will be performed between -30 and -7 days prior to treatment in all subjects. All subjects will undergo a post-treatment biopsy on day 180. Micro-dystrophin gene expression was quantified (immunofluorescence and Western blot analysis) and compared before and after muscle biopsy.	6 months